It is our working hypothesi that ethanol-induced open field activity (OFA) and D2 dopamine receptor binding are genetically correlated characters. We further propose that individuals with increased post-synaptic and/or decreased presynaptic receptor density will show an activation response to ethanol associated. We predict it will be possible to detect common genetic mechanisms. To accomplish this goal, we propose to simultaneously map the quantitative trait loci (QTL) for both phenotypes. The specific aims of the proposal may be summarized: 1. To conduct a genome wide QTL search in a C57BL/6J (B6) x DBA/2J (D2) F2 cross (N=500) phenotyped for both ethanol-induced OFA and D2 receptor binding. Genotyping will first be performed only on the phenotypic extremes (the top and bottom 12% ) using polymorphic microsatellites. The B6XD2 cross was chosen because the parental strains are highly polymorphic, because of the marked behavioral difference between the parental strains for ethanol-induced OFA and because of the large number of ethanol behavioral phenotypes for which a QTL analysis has been performed in the BXD recombinant inbred (RI) series. There are strong reasons to believe that some of these behavioral QTLs and dopamine receptor QTLs will be identical. To confirm and expand the search for OFA and receptor QTLs, we propose - 2. To conduct a genome wide QTL search in a BALB/cJ (C) x LP/J (LP) F2 cross (N=500) phenotyped for both ethanol-induced OFA and D2 receptor binding. The CXLP F2 cross was chosen because the parental strains are highly polymorphic and because among inbred mouse strains, the parental strains appear to be at the extremes of the distribution for D2 receptor density . The QTL analysis here will be used both to confirm the "B6D2" QTLs and to search for additional QTLs which are not associated with the B6D2 genotypes. The sample size and general research strategy are identical to that in specific aim 1. For the QTLs with the largest effect sizes and especially for the QTLs common to both phenotypes and to specific aims 1 and 2, we propose - 3. To genotypically select F2 animals for these QTLs and examine the effect(s) of such selection on the two phenotypes of interest. This selection will provide additional QTL confirmation and will provide the justification for the formation of congenic strains, an important first step towards the positional cloning of the relevant genes. The analyses described in specific aims 1-3 make no assumptions about the genomic locations of the QTLs. However, preliminary data from this laboratory and elsewhere suggest that an important QTL will be either near or part of Drd2 on chromosome 9.